CN105311016A - Anti-apoptosis Mcl-1 protein inhibitor, and applications thereof - Google Patents
Anti-apoptosis Mcl-1 protein inhibitor, and applications thereof Download PDFInfo
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- ILEDWLMCKZNDJK-UHFFFAOYSA-N Oc(cc(C=CC(O1)=O)c1c1)c1O Chemical compound Oc(cc(C=CC(O1)=O)c1c1)c1O ILEDWLMCKZNDJK-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses an anti-apoptosis Mcl-1 protein inhibitor, and applications thereof, and belongs to the field of medical technology. The anti-apoptosis Mcl-1 protein inhibitor is a 6,7-dihydroxycoumarin derivative, and the general structure is represented by formula (I), wherein R1 and R2 are used for representing H or (C1-C6) alkyl groups, R3 is used for representing H or CH2NR5R6, NR5R6 is one randomly selected from dimethylamine, diethylamine, dipropyl amine, diisopropylamine, pyrrolidine, piperidine, morpholine, piperazine, or structure derivatives thereof, R4 is used for representing one randomly selected from H, (C1-C6) alkyl groups, CF3, OH-(C1-C6) alkyl groups, and halogenated-(C1-C6) alkyl groups. The anti-apoptosis Mcl-1 protein inhibitor is used for inducing cell apoptosis via competitive binding and antagonism with Mcl-1 protein, killing tumor cells, and can be taken as an anticancer medicine. The anti-apoptosis Mcl-1 protein inhibitor is low in molecular weight, excellent in membrane permeable performance, and high in safety, and possessing a promising prospect in development of medicines.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of anti-apoptotic Mcl-1 protein inhibitor and application thereof.
Background technology
Essence and the basic process of cancer generation development are just progressively disclosed, and have become the dominant direction of antitumor drug research for its molecular targeted new type antineoplastic medicine that development mechanism occurs.In recent years, some are using the relevant key protein of tumor cell differentiation apoptosis as drug screening target spot, find efficient in target site of selectively acting, low toxicity, the new type anticancer medicine of high specificity has become the another new direction of current antineoplastic medicine research and development.
Bcl-2 family protein plays very important effect in apoptotic regulation and control.This family protein comprises the contrary albumen of two class functions: a class is anti-apoptotic proteins, comprises more than ten members such as Bcl-2, Mcl-1, Bcl-xl and Bcl-w; Another kind of is pro apoptotic protein, comprises Bax, Bak, Bad and Bim etc.The albumen such as Mcl-1 also exist the surface combination pocket of a BH3 by name, can with many short antiapoptotic factors, as Bax, Bad, Bim and Bak etc. combine and form heterodimer, suppress their short apoptosis function, cause apoptotic infringement [NatRevCancer, 2002,2:647-656].Research finds, in cell, Mcl-1/Bcl-2 protein abnormal expression is relevant with the generation of kinds cancer, nearly all malignant cell is high expressed Mcl-1/Bcl-2 albumen all, and normal tissue cell Mcl-1/Bcl-2 expression very low [JCellBio.2008,180:341-355; CancerRes, 2006,66:9636-9645].Mcl-1/Bcl-2 albumen has been develop the new drug target of of cancer therapy drug in the world, and its research and development mainly concentrate on and how to suppress Mcl-1/Bcl-2 protein active or reduce its expression, carry out the apoptosis of induced cancer cell.
At present, commercialized product is there is no with the antitumor drug that Bcl-2 family protein is target spot, what have three effect optimums is in clinical I respectively, II, the III phase, respectively: the AB-737 researched and developed by Illinoi State, The United States Alpert laboratory, the GX15-070 (K protein bound with Bcl-2 of GeminX company research and development
i=0.22 μM) and the AT-101 (K protein bound with Mcl-1 of Ascenta company of the U.S.
i=0.18 μM).But they are Shortcomings all, as GX15-070 has the cytotoxicity not relying on Bax/Bak, just therefore on the verge of being replaced.In addition, and the inhibit activities in body is on the low side, metabolic half life is short, continuous use easily causes many defects such as liver, nephrotoxicity.Therefore, explore and develop the medicine of safety, efficiently specific antagonist Mcl-1/Bcl-2 albumen, specificity inhibition tumor cell grows, and the injury of normal tissue cell is very little, finally realizes the target that safe, efficient, low misery is anticancer.
Summary of the invention
For the problems referred to above, the invention provides a kind of anti-apoptotic Mcl-1 protein inhibitor and application thereof.
A kind of anti-apoptotic Mcl-1 protein inhibitor and application, it is characterized in that described inhibitor is Esculetin derivant, its structure such as general formula is:
Wherein, R
1, R
2for H or (C
1-C
6) alkyl;
R
3for H or CH
2nR
5r
6;
NR
5r
6for any one in dimethylamine, diethylamine, di-n-propylamine, diisopropylamine, pyrrolidine, piperidines, morpholine, piperazine or its structural derivative;
R
4for H, (C
1-C
6) alkyl, CF
3, OH-(C
1-C
6) alkyl, halo-(C
1-C
6) any one in alkyl.
The equal contestable of any one or a few compound of described inhibitor Esculetin derivant combines and antagonism Mcl-1 albumen, and cell death inducing, realize its application as anticancer compound and suppress constant K
ivalue is between 0.2 ~ 15 μM.
An application for anti-apoptotic Mcl-1 protein inhibitor, by any one or a few compound of Esculetin derivant and chemotherapeutics by making pharmaceutical composition after mixing and being used for the treatment of cancer.
Described Esculetin derivant and paclitaxel make pharmaceutical composition and for the treatment of nonsmall-cell lung cancer, its mol ratio share is 1:5 ~ 10:1, and preferred molar ratio is 1 ~ 5:1.
Novel Mcl-1 protein inhibitor involved in the present invention, with 6 of plant origin, 7-dihydroxycoumarin is basic structure skeleton, by the multidimensional property assessment of the structure-drug effect of series compound, structure-safety, structure-ADME attribute and optimize, have developed above-mentioned novel Mcl-1 protein inhibitor, such inhibitor and the protein bound K of Mcl-1
ireach 0.204 μM, its inhibit activities and commercially available Mcl-1 inhibitor AT-101 (K
i=0.18 μM) activity suitable, even higher than TW-37 (K
i=0.26 μM) inhibit activities.In addition, such inhibitor and paclitaxel coupling significantly can increase the inhibit activities of paclitaxel to A549 cell.Meanwhile, such inhibitor also has the features such as drug-resistant protein, reversible tumor multi-medicine drug-resistant such as good, the easy absorption of safety and potent suppression P-gp, has good patent medicine prospect.
Accompanying drawing explanation
Fig. 1. the concentration dependent that Compound C-3 pairs of Mcl-1 albumen suppress suppresses figure;
Fig. 2 .6,7-dihydroxy derivant structure-Mcl-1 protein inhibiting activity graph of a relation;
Fig. 3. Compound C-3 and paclitaxel coupling are to the inhibit activities figure of A549 cell.
Detailed description of the invention
The following examples will be further described the present invention, but not thereby limiting the invention.
The multi-functional microplate reader of main detecting instrument and model thereof: GENios (TECAN company, Switzerland), horizontal laminar flow superclean bench (Shanghai), HHCP-T carbon dioxide cell incubator (Shanghai Yi Heng experimental apparatus company limited), FP-6500 spectrofluorophotometer (Jasco company, Japan), Mcl-1 antibody (BS1220, Bioworld biotech company, the U.S.), horseradish peroxidase labelling two anti-(34460, Qiagen biotech company, Germany).
Embodiment 1
The preparation of 6,7-dihydroxy-4-methylcoumarin (C-2)
Take 1,2,4-triacetoxyl group benzene 1.5g and be placed in there-necked flask, add ethyl acetoacetate 1ml, perchloric acid 5ml, stirring at room temperature is after 20 minutes, be heated to 80 DEG C, reaction 3h, TLC detection reaction terminates, and is slowly poured into by reactant liquor in frozen water 30ml, stir 30min, filter, collect filter cake, be crude product.Crude product is dissolved in 20ml methanol, is heated to backflow, after 1h, is cooled to room temperature, filter, collect filter cake, obtain Compound C-21.1g after vacuum drying, Off-white solid.
Its magnetic resonance detection result is as follows:
1HNMR(400MHz,d-DMSO)δ:2.31(s,3H,CH
3),6.09(s,1H,C＝CH),6.73(s,1H,ArH),7.00(s,1H,ArH),9.34(s,br,1H,ArOH),10.19(s,br,1H,ArOH)；
13CNMR(100MHz,d-DMSO)δ:18.68,103.13,109.89,110.86,111.96,143.24,148.17,150.58,153.68,161.08.
Embodiment 2
The preparation of 6,7-dihydroxy-4-trifluoromethyl coumarin (C-3)
Take 1,2,4-triacetoxyl group benzene 1.5g and be placed in there-necked flask, add trifluoroacetic ethyl acetoacetate 1.4ml, perchloric acid 5ml, stirring at room temperature is after 20 minutes, be heated to 80 DEG C, reaction 3h, TLC detection reaction terminates, and is slowly poured into by reactant liquor in frozen water 30ml, stir 30min, filter, collect filter cake, be crude product.Crude product is dissolved in 20ml methanol, is heated to backflow, after 1h, is cooled to room temperature, filter, collect filter cake, obtain Compound C-31.3g after vacuum drying, light yellow solid.Its magnetic resonance detection result is as follows:
1HNMR(400MHz,d-DMSO)δ:6.71(s,1H,C＝CH),6.86(s,1H,ArH),7.03(s,1H,ArH),9.78(s,br,1H,ArOH),10.61(s,br,1H,ArOH)；
13CNMR(100MHz,d-DMSO)δ:104.01,105.05,108.89,112.12,120.94,123.68,144.03,149.59,152.08,159.62.
Embodiment 3
The preparation of 6,7-dihydroxy-4-chloromethyl coumarin (C-4)
Take 1,2,4-triacetoxyl group benzene 1.5g and be placed in there-necked flask, add 4-chloroacetyl acetacetic ester 1.3ml, perchloric acid 5ml, stirring at room temperature is after 20 minutes, be heated to 80 DEG C, reaction 3h, TLC detection reaction terminates, and is slowly poured into by reactant liquor in frozen water 30ml, stir 30min, filter, collect filter cake, be crude product.Crude product is dissolved in 20ml methanol, is heated to backflow, after 1h, is cooled to room temperature, filter, collect filter cake, obtain Compound C-31.2g after vacuum drying, Off-white solid.
Its magnetic resonance detection result is as follows:
1HNMR(400MHz,d-DMSO)δ:4.90(s,2H,CH
2Cl),6.40(s,1H,C＝CH),6.78(s,1H,ArH),7.12(s,1H,ArH),9.48(s,br,1H,ArOH),10.39(s,br,1H,ArOH).
Embodiment 4
The preparation of 6,7-dihydroxy-4-hydroxymethylcoumarin (C-5)
Take 6,7-dihydroxy-4-chloromethyl coumarin 500mg and be placed in single port bottle, add DMF 1.0ml, water 5ml, be heated to backflow, reaction 20h, TLC detection reaction terminates, and has solid to separate out, filters, collect filter cake, be crude product after cooling.Crude product is dissolved in 2ml methanol, is heated to backflow, after 0.5h, is cooled to room temperature, filter, collect filter cake, obtain Compound C-5200mg after vacuum drying, brown solid.
Its magnetic resonance detection result is as follows:
1HNMR(400MHz,d-DMSO)δ:4.63(s,2H,CH
2OH),6.21(s,1H,C＝CH),6.75(s,1H,ArH),6.94(s,1H,ArH),9.31(s,br,1H,ArOH),10.19(s,br,1H,ArOH).
Embodiment 5
The preparation of 6,7-dimethoxy coumarin (C-9)
Take Esculetin 1.0g and be placed in there-necked flask, add N, dinethylformamide 5.0ml, potassium carbonate 2.1g, iodomethane 1.2ml, 25 DEG C of reaction 8h, TLC detection reaction terminate, and add water 40ml quencher reaction, ethyl acetate 30mlx3 extracts, combined ethyl acetate phase, washing 30mlx2, anhydrous sodium sulfate drying, filters, by solvent under reduced pressure evaporate to dryness, residue silica gel column chromatography is separated, and obtains Compound C-90.95g, light yellow solid.
Its magnetic resonance detection result is as follows:
1HNMR(400MHz,d-DMSO)δ:3.80(s,3H,CH
3O),3.86(s,3H,CH
3O),6.29(d,J＝8.0Hz,1H,COCH＝C),7.06(s,1H,ArH),7.25(s,1H,ArH),7.95(d,J＝8.0Hz,1H,C＝CH).
13CNMR(100MHz,d-DMSO)δ:56.34,56.63,100.50,109.38,111.64,113.11,144.79,146.31,149.88,152.99,161.01.
Embodiment 6
The preparation of 6,7-dihydroxy-8-(methylene dimethylamino) coumarin (C-10)
Take 6,7-dihydroxycoumarin 0.9g is dissolved in 40ml methanol, add 37% formalin 1.0ml, 30% dimethylamine agueous solution 0.8ml, is heated to 35 DEG C of reaction 8h, TLC detection reaction and terminates, by solvent under reduced pressure evaporate to dryness, residue silica gel column chromatography is separated (eluant is dichloromethane: methanol=10:1 ~ 3:1), obtains Compound C-10180mg, yellow-brown solid.
Its magnetic resonance detection result is as follows:
1HNMR(400MHz,d-DMSO)δ:2.49(s,6H,2CH
3),4.03(s,2H,CH
2),6.03(d,J＝8.0Hz,1H,ArH),6.86(s,1H,ArH),7.79(d,J＝12.0Hz,1H,ArH),8.16(s,1H,ArOH).
Embodiment 7
The preparation of 6,7-dihydroxy-8-(1-methylene pyrrole alkyl) coumarin (C-11)
Take 6,7-dihydroxycoumarin 1.8g is dissolved in 90ml methanol, add 37% formalin 1.6ml, pyrrolidine 0.9ml, is heated to 65 DEG C of reaction 8h, TLC detection reaction and terminates, by solvent under reduced pressure evaporate to dryness, residue silica gel column chromatography is separated (eluant is dichloromethane: methanol=10:1 ~ 3:1), obtains Compound C-11600mg, yellow-brown solid.
Its magnetic resonance detection result is as follows:
1HNMR(400MHz,d-DMSO)δ:1.85(m,4H,CH
2CH
2),2.88(t,J＝4.8Hz4H,NCH
2CH
2),4.17(s,2H,CH
2),5.97(d,J＝8.0Hz,1H,ArH),6.82(s,1H,ArH),7.76(d,J＝8.0Hz,1H,ArH).
13CNMR(100MHz,d-DMSO)δ:23.05(2C),49.88,52.84(2C),105.98,107.16,107.75,109.05,143.49,144.90,147.58,156.57,160.86.
Embodiment 8
The preparation of 6,7-dihydroxy-8-(1-methylene-4-hydroxy piperidine) coumarin (C-12)
Take 6,7-dihydroxycoumarin 1.0g is dissolved in 50ml methanol, add 37% formalin 0.9ml, 4-hydroxy piperidine 0.4ml, is heated to 50 DEG C of reaction 10h, TLC detection reaction and terminates, by solvent under reduced pressure evaporate to dryness, residue silica gel column chromatography is separated (eluant is dichloromethane: methanol=10:1 ~ 3:1), obtains Compound C-12300mg, yellow-brown solid.
Its magnetic resonance detection result is as follows:
1HNMR(400MHz,d-DMSO)δ:1.48(m,2H,CH
2),1.82(m,2H,CH
2),2.49(m,2H,NCH
2),2.91(m,2H,NCH
2),3.62(m,1H,CHOH),4.00(s,2H,CH
2),6.08(d,J＝8Hz,1H,ArH),6.89(s,1H,ArH),7.81(d,J＝8Hz,1H,ArH).
13CNMR(100MHz,d-DMSO)δ:33.50,49.72,52.56,106.77,108.87,109.71,110.38,142.79,144.87,146.79,153.60,160.62.
Embodiment 9
The preparation of 4-methyl-6,7-dihydroxy-8-(methylene dimethylamino) coumarin (C-13)
Take 4-methyl-6,7-dihydroxycoumarin 0.9g is dissolved in 40ml methanol, add 37% formalin 1.0ml, 30% dimethylamine agueous solution 0.8ml, is heated to 50 DEG C of reaction 8h, TLC detection reaction and terminates, by solvent under reduced pressure evaporate to dryness, residue silica gel column chromatography is separated (eluant is dichloromethane: methanol=10:1 ~ 3:1), obtains Compound C-13800mg, faint yellow solid.
Its magnetic resonance detection result is as follows:
1HNMR(400MHz,d-DMSO)δ:2.30(s,3H,CH
3),2.42(s,6H,2CH
3),4.00(s,2H,CH
2),5.99(s,1H,ArH),6.92(s,1H,ArH)；
13CNMR(100MHz,d-DMSO)δ:18.87,43.83,54.51,106.93,107.48,108.82,109.27,143.39,146.82,154.21,155.03,160.98.
Embodiment 10
The preparation of 4-methyl-6,7-dihydroxy-8-(1-methylene pyrrole alkyl) coumarin (C-14)
Take 4-methyl-6,7-dihydroxycoumarin 1.8g is dissolved in 90ml methanol, add 37% formalin 1.6ml, pyrrolidine 0.9ml, is heated to 65 DEG C of reaction 6h, TLC detection reaction and terminates, by solvent under reduced pressure evaporate to dryness, residue silica gel column chromatography is separated (eluant is dichloromethane: methanol=10:1 ~ 3:1), obtains Compound C-141.4g, yellow-brown solid.
Its magnetic resonance detection result is as follows:
1HNMR(400MHz,d-DMSO)δ:1.84(m,4H,2CH
2),2.29(s,3H,CH
3),2.83(m,4H,2NCH
2),4.15(s,2H,CH
2),5.96(s,1H,ArH),6.89(s,1H,ArH)；
13CNMR(100MHz,d-DMSO)δ:18.89,23.60,50.17,53.33,106.97,108.32,108.70,143.65,146.90,154.23,155.87,161.07.
Embodiment 11
The preparation of 4-methyl-6,7-dihydroxy-8-(1-methylene-4-hydroxy piperidine) coumarin (C-15)
Take 4-methyl-6,7-dihydroxycoumarin 1.0g is dissolved in 50ml ethanol, add 37% formalin 0.9ml, 4-hydroxy piperidine 0.4ml, is heated to 80 DEG C of reaction 10h, TLC detection reaction and terminates, by solvent under reduced pressure evaporate to dryness, residue silica gel column chromatography is separated (eluant is dichloromethane: methanol=10:1 ~ 3:1), obtains Compound C-15750mg, yellow-brown solid.
Its magnetic resonance detection result is as follows:
1HNMR(400MHz,d-DMSO)δ:1.47(m,2H,CH
2),1.81(m,2H,CH
2),2.31(s,1H,CH
3),2.45(m,2H,NCH
2),2.87(m,2H,NCH
2),3.61(m,1H,CHOH),3.99(s,2H,CH
2),6.04(s,1H,ArH),6.94(s,1H,ArH).
13CNMR(100MHz,d-DMSO)δ:18.30,33.61,49.77,52.88,107.02,107.58,109.18,109.77,142.49,145.82,152.80,153.61,160.32.
Embodiment 12
Series compound is to the suppression constant K of Mcl-1 albumen
ivalue (fluorescence polarization detection)
1) synthesize one with 21 amino acid whose BidBH3 peptide sections (aminoacid: 79-99:QEDIIRNIARHLAQVGDSMDR), and to hold on labelling 6-CF 5(6)-Carboxyfluorescein succinimide ester (FAM) as fluorescence labels (FAM-Bid) at N.
2) in competion experiment, reaction system used is that GST-Mcl-1 albumen (40nM) and FAM-Bid polypeptide (5nM) are dissolved in reaction buffer (100mMK
3pO
4, pH7.5; 100 μ g/mL cattle γ albumin; 0.02% Hydrazoic acid,sodium salt).In 96 orifice plates, every hole adds 100 μ L reaction systems, then adds the solution that 1 μ L is dissolved in the compound to be detected of DMSO variable concentrations (10mM-10 μM).
3) set up two matched groups, a matched group is only containing Mcl-1 and FAM-Bid (being equivalent to 0% suppression ratio) in reaction system, and the reaction system in another matched group is only containing FAM-Bid peptide section simultaneously.
4) 96 orifice plates are after the lucifuge of 4 hours is hatched, and carry out microplate reader detects.Fluorescence polarization value (mP) is measured under the 485nm emission wavelength exciting generation by 530nm wavelength.Albumen suppression ratio is utilized to obtain IC to the mapping of compound dosage logarithm
50value, according to formula K
i=[I]
50/ ([L]
50/ K
d+ [P]
0/ K
d+ 1) derivation calculates K
ivalue, as shown in table 1.
Table 1 series compound is to the suppression constant K of Mcl-1 albumen
ivalue
By summing up analysis of experimental data, establish Esculetin derivant structure-Mcl-1 protein inhibiting activity relation (as shown in Figure 2).Introduce electron withdraw group for 4 at compound Esculetin, Mcl-1 albumen antagonistic activity increases, as Compound C-3, C-4 and C-5; Introduce lipophilic group for 4 at compound Esculetin, Mcl-1 albumen antagonistic activity increases too, and as Compound C-2, C-3 and C-6, Compound C-3 pairs of Mcl-1 albumen antagonistic activities with dual function are the strongest.The catechol group of Esculetin is extremely important to Mcl-1 albumen antagonistic activity, and the hydroxyl of catechol is replaced rear activity by alkyl all to be reduced, as Compound C-7, C-8 and C-9; Introduce containing N hydrogen bond receptor for 8 at Esculetin, after forming intramolecular hydrogen bond with 7-hydroxyl, activity also all reduces, as Compound C-10 ~ C-15.
Embodiment 13
Adopt srb assay detection compound C-3 and paclitaxel coupling to the inhibit activities of A549 cell.
Cell is inoculated in the RPMI1640 culture fluid containing 10% new-born calf serum, puts 37 DEG C, 5%CO
2cultivate with under complete wet condition.Test when cell reaches exponential phase.Be inoculated in 96 orifice plates by A549 cell, inoculum density is respectively: 6500/ hole/100ulRPMI1640, in CO
224h is hatched in incubator.Afterwards, adding Compound C-3 and the mixture (mol ratio is for being respectively 0.5:1,1:1,2:1) of paclitaxel, making final concentration be respectively 100,10,1,0.1,0.01,0.001,0.0001 μm/L; Adopt the paclitaxel of same final concentration as positive control simultaneously; Matched group adds the RPMI1640 that equal-volume contains 1% dimethyl sulfoxide (DMSO); Blank group only has culture fluid not add cell, and often group establishes 3 multiple holes.After cultivating 48h, srb assay detects the survival rate of cell.Every hole adds the trichloroacetic acid (TCA) of the pre-cooling of 50ul50%, 96 orifice plates be placed in-4 DEG C one hour, after cold water cleans five times, SRB in 37 DEG C dyeing 30min.The SRB into combining washed by 1% acetic acid, and dry the dyestuff that rear use Tris (10mM, pH10.5) dissolving combines, microplate reader measures absorbance (A value) under 570nm, calculates growth inhibition ratio (IR).IR (%)=[1-(experimental group A value-blank group A value)/(control group A value-blank group A value)] × 100%.Experiment repetition 3 times.Compound C-3 is as shown in table 2 with the inhibit activities of paclitaxel coupling to A549 cell.Compound C-3 and paclitaxel coupling (mol ratio is 2:1) are to the inhibit activities of A549 cell as shown in Figure 3
Table 2 Compound C-3 and paclitaxel coupling are to the inhibit activities of A549 cell
Claims (4)
1. an anti-apoptotic Mcl-1 protein inhibitor, is characterized in that described inhibitor is Esculetin derivant, and its structure such as general formula is:
Wherein, R
1, R
2for H or (C
1-C
6) alkyl;
R
3for H or CH
2nR
5r
6;
NR
5r
6for any one in dimethylamine, diethylamine, di-n-propylamine, diisopropylamine, pyrrolidine, piperidines, morpholine, piperazine or its structural derivative;
R
4for H, (C
1-C
6) alkyl, CF
3, OH-(C
1-C
6) alkyl, halo-(C
1-C
6) any one in alkyl.
2. according to the application of a kind of anti-apoptotic Mcl-1 protein inhibitor according to claim 1, it is characterized in that described inhibitor 6, the equal contestable of any one or a few compound of 7-dihydroxycoumarin derivant combines and antagonism Mcl-1 albumen, and cell death inducing, realize its application as anticancer compound, suppress constant K
ivalue is between 0.2 ~ 15 μM.
3. according to the application of a kind of anti-apoptotic Mcl-1 protein inhibitor according to claim 1, it is characterized in that described 6,7-dihydroxycoumarin derivant and paclitaxel make pharmaceutical composition and for the treatment of nonsmall-cell lung cancer, Esculetin derivant and paclitaxel mol ratio are 1/5 ~ 10:1.
4. according to the application of a kind of anti-apoptotic Mcl-1 protein inhibitor according to claim 3, it is characterized in that described 6,7-dihydroxycoumarin derivant and paclitaxel make pharmaceutical composition and for the treatment of nonsmall-cell lung cancer, Esculetin derivant and paclitaxel preferred molar ratio are 1 ~ 5:1.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018127575A1 (en) * | 2017-01-06 | 2018-07-12 | Les Laboratoires Servier | Combination of a mcl-1 inhibitor and a taxane compound, uses and pharmaceutical compositions thereof |
| IL267791A (en) * | 2017-01-06 | 2019-09-26 | Novartis Ag | Combination of a mcl-1 inhibitor and a taxane compound, uses and pharmaceutical compositions thereof |
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| CN104606186A (en) * | 2014-11-19 | 2015-05-13 | 北京工业大学 | Application of fluoro-7-hydroxycoumarin compound in protein kinase inhibitor or/and antitumor drug |
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| TWI674898B (en) * | 2017-01-06 | 2019-10-21 | 法商施維雅藥廠 | Combination of a mcl-1 inhibitor and a taxane compound, uses and pharmaceutical compositions thereof |
| US10765680B2 (en) | 2017-01-06 | 2020-09-08 | Les Laboratories Servier | Combination of a MCL-1 inhibitor and a taxane compound, uses and pharmaceutical compositions thereof |
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